Measles remains a significant public health concern, and the WHO and the NIH have set as a priority the need to understand the irnmunogenetics of vaccine response. In our ongoing studies we have demonstrated significant associations between measles vaccine virus (MVV)-induced antibody levels and specific HLA alleles. We now propose a series of experiments designed to understand, at the HLA-peptide interaction level, the molecular immunogenetic mechanisms that affect immune responsiveness to immunization. Our broad goal is to identify the unique spectrum of MVV peptides bound by class II HLA-DR molecules associated with measles vaccine "non-", and "hyper-response", and, in turn, to demonstrate that differences in this spectrum of unique measles vaccine-derived peptides- presented by specific HLA molecules - are associated with differences in humoral and cell-mediated immune responses. To accomplish this goal, we propose the following specific aims: In Specific Aim # I we will identify and sequence the MVV-derived peptides bound in the peptide binding grove of class II HLA-DR4 and DR3 molecules using novel mass spectrometry techniques. In Specific Aim # 2 we will measure the effect of specific peptides versus specific HLA molecules by determining the immunologic relevance and functional specificity of the above identified MVV-derived peptides in human PBMCs expressing DR4 and DR3 molecules, as well as "screen" peptides by measuring lymphoproliferative responses in response to individual MVV peptides. The major biologic concept around which our work and this proposal is centered is that the ability to respond to a vaccine antigen is predominantly determined by genetic polymorphism of the HLA genes. Because each HLA allele binds a distinct set of peptides, this proposal specifically focuses on using a biochemical approach to identify the distinct spectrum of peptides bound in the HLA peptide binding groove of "non-"and "hyper"-antibody responders" after receiving measles vaccine and determining the immunologic relevance of these peptides. An enchanced understanding of the interaction of peptide:HLA molecules in producing an immune response will result, allowing molecular design strategies for vaccines against human pathogens. The basis from which this proposal will build on is outlined in the background, significance, and preliminary data sections below.